PB1849: EARLY SALVAGE THERAPY WITH VENETOCLAX AND 10-DAY DECITABINE IS FEASIBLE AND SAFE IN REFRACTORY AML: RESULTS FROM 11 PATIENTS WITH EARLY INDUCTION FAILURE
Authors: Carla Borst, Franziska Ginsberg, Jan Weller, Wichard Vogel, Christoph Faul, Wolfgang Bethge, Maximilian Christopeit, Claudia Lengerke
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: Primary induction failure (PIF)/primary refractory disease in Acute Myeloid Leukemia (AML) has been originally defined as failure to reach complete hematologic remission (CR, <5% bone marrow blasts) after two cycles of induction chemotherapy. PIF affects 20% of patients with newly diagnosed AML. Patients failing to clear blasts (<5%) after the first induction chemotherapy cycle are at high risk of PIF and show inferior overall, event free and relapse-free survival. Increasing chemotherapy intensity in patients with PIF proofed to be futile. However, this may change with modern salvage strategies incorporating targeted agents. The BCL2 inhibitor Venetoclax employs a complementary mode of action and shows promising efficacy in AML with various molecular backgrounds. Aims: We hypothesized that combined treatment with Venetoclax and Decitabine can target hypoproliferative and chemotherapy resistant AML cells more effectively than (intensified) classic salvage chemotherapy regimens such as FlAG-Ida, HAM or a second cycle of intensive induction treatment, thus enabling patients to proceed to allogeneic stem cell transplantation (ASCT) with a lower leukemic cell load. We propose that application of a 10-day Decitabine/Venetoclax (Deci(10)/Ven) treatment started immediately after detection of unsuccessful blast clearance is feasible and safe. Methods: Adult patients with AML and primary induction failure (defined as ≥10% leukemic blasts in bone marrow on day 15 or ≥5% leukemic blasts in bone marrow on day 28 after start of induction therapy) received salvage therapy with Decitabine 20mg/m² for 10 days i.v. combined with Venetoclax, ramped up 100 mg day 1, 200 mg day 2, 400mg from day 3 on, administered for 28 days in total. Patients eligible for intensive therapy were subsequently treated with ASCT. Results: A total number of 11 patients with AML were treated, among which 7 patients with adverse, 2 with intermediate and 2 with good risk disease according to ELN criteria. The median age at diagnosis was 55 years. All patients received one cycle of Deci(10)/Ven. 5 patients received a second cycle Deci(5)/Ven (Decitabine for 5 days), one patient had a third cycle of Deci(5)/Ven. 7 of 11 (63%) patients achieved hematologic CR, of which 5 patients after one cycle. One patient had partial response and 2 patients showed persistency of leukemic blasts. Median duration of neutropenia (absolute neutrophile count <500/µl) was 39 days from start of Deci(10)/Ven. Grade III/IV infections occurred in 3 patients. Subsequent ASCT was performed in 8 patients and is currently scheduled for 2 patients, one patient refused further therapy. Median time to transplant was 67 days from start of Deci(10)/Ven. One patient received ASCT without prior neutrophil recovery. Conditioning regimens included Bu/Cy, FLAMSA, Flu/Treo, Flu/TBI. CR after ASCT was documented in 8/8 already treated patients, of which 4/8 remained relapse-free at current follow-up. 9 out of 11 patients are still alive. Summary/Conclusion: Salvage therapy with Deci(10)/Ven in AML patients with early induction failure is a feasible and safe alternative to classic chemotherapy based salvage therapies. Early response assessment (e.g. on day 15 after start of the first induction) with immediate salvage therapy of Deci(10)/Ven beginning 30 days on average after start of induction treatment may lead to a higher response rate. All 11 patients had manageable side effects enabling subsequent ASCT in a high proportion of patients with hematologic CR. Further studies are needed to show whether patients without hematologic CR profit from further cycles of Deci/Ven. Based on these data, we will initiate a clinical trial further evaluating Venetoclax/Decitabine salvage therapy in PIF AML at our center. Keywords: Allogeneic stem cell transplant, Acute myeloid leukemia, decitabine, Venetoclax